In the past decades there has been a great interest in the use of end group functionalized polyethylene glycol for the modification of peptides, proteins, enzymes and non-peptide drugs. For instance, A. Abuchowski et al. in J. Biol. Chem., 252, 3578-3581 (1977) and in Cancer Biochem. Biophys., 7, 175-186 (1984) described modifying a protein by means of polyethylene glycol grafted onto amino side groups along the said protein. It was shown by S. Zalipsky, Bioconjugate Chem. 6, 150-165 (1995) and by C. Delgado et al., Critical Reviews in Therapeutic Drug Carrier Systems, 9, (3,4), 249-304 (1992) that polyethylene glycol grafted proteins exhibit a longer plasma half-life in vivo, are less immunogenic and more thermostable.
Zalipsky (cited above), Delgado (cited above), T. M. Allen et al. in Biochimica et Biophysica Acta, 1237, 99-108 (1995), J. M. Harris, Ed. Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, ed., Plenum Press, New York, 1992, and G. Hooftman et al. in J. Bioact. Biocomp. Polymers, 11, 135-159 (1996) have reviewed a variety of methods for introducing reactive groups at the chain end of polyethylene glycol which can react in a selective manner with protein functional side groups such as amino, thiol, guanidyl and the like.
Recently, polyethylene glycol has been used for the modification of synthetic vectors for gene delivery in order to prevent complexes with DNA from interactions with plasma proteins and erythrocytes and from enzymatic degradation in extra- and intracellular compartments (see for instance M. Ogris et al., Gene Therapy (1999) 6:595-605).
In biomaterial science, grafting of a polymer material surface with polyethylene glycol chains (hereinafter referred to as “PEG-ylation”) has been extensively described as a method for improving surface biocompatibility. Surface PEG-ylation can be achieved by chemical grafting of polyethylene glycol onto a pre-formed surface as well as by applying a polymer having polyethylene glycol as a building part of its backbone or alternatively as a grafted side group. Such polymers can be used as a core material or be applied as a surface coating.
Polyethylene glycol is a rather stable polymer which is a repellent of protein adhesion and which is not subject to enzymatic or hydrolytic degradation under physiological conditions. However, biomedical applications are at every time looking for improved biocompatible polymeric materials. In particular, there is concern that polyethylene glycol, being not biodegradable, has difficulties to escape from cells and could be stored in cells, according to J. Lloyd, Biochem.J., 261, 451-456 (1989). Therefore there is a need in the art for substituting polyethylene glycol, in such biomedical applications, by a polymer having similar properties but which is biodegradable. In another area, there is a need for the permanent grafting of polymer chains onto a polymer material surface. The above mentioned problems will be solved by the polymer and copolymer derivatives as described in this invention, containing functionalities that can be used to attach bioactive substances, e.g. short peptide molecules such as the tripeptide RGD (arginine-glycine-aspartic acid) and the like, or saccharides and oligosaccharides such as mannose and galactose. In yet another area, an object of the present invention is to provide improved synthetic vectors to serve as carrier vehicles for efficient and effective delivery of nucleic acid material, and transfection of target cells, especially in connection with gene therapy or even possibly in connection with development of DNA vaccines.